Background: Immediate antibiotic allergic response is an important public health
problem. Genetic and molecular characterization will improve treatment
outcomes for truly allergic patients, and also reduce the use (and risk of
evolution of pathogen resistance) of second-line antibiotics given to patients
who incorrectly believe themselves to be allergic to first-line antibiotics.
Objective: To identify genetic and metabolic factors associated with allergic
responses to beta-lactam antibiotics using the TwinsUK cohort and recruited
participants from the Guy’s allergy clinic.
Methods: The TwinsUK cohort is the largest registry of adult twins in the UK, and
the Guy’s allergy clinic is an outsized clinic covering a large area of the UK. The
TwinsUK cohort has been extensively molecularly characterized. After
characterising the heritability, we conducted the first high-coverage genomewide
association study (GWAS) between 211 self-reported cases in the TwinsUK
cohort with questionnaire-defined beta-lactam allergic status and over 1000
individuals without self-reported allergic reaction to any substances.
Approximately 2.1 million imputed and genotyped single nucleotide
polymorphisms were investigated. A second GWAS was conducted on 48
clinically proven cases from the Guy’s Hospital allergy clinic and ~6000
population controls. In addition a metabolome-wide association study (MWAS)
was conducted on the same TwinsUK registry individuals, scanning 510 different
Results: Following refinement of the self-reported beta-lactam allergy phenotype
via the application of a more detailed questionnaire, we estimated a heritability
of 21%. The heritability estimates provided positive evidence for a genetic
component for beta-lactam allergy. A single hit from the TwinsUK GWAS at the
MTHFS/BCL2A1 locus was found (p<5x10-8 ), indicating a provisional “genomewide
significant” hit. Results from the TwinsUK MWAS demonstrated that all
metabolites responded as a correlated system to the differences among twins in
their allergy status. There were also 4 distinct “metabolome-wide significant”
hits, of which two corresponded to known metabolites, suggesting that people
who had penicillin allergy had less piperine in their system in comparison with
our control group and had higher amounts of 4-vinylphenol-sulfate metabolite.
Conclusion: This study demonstrated a genetic component to beta-lactam
allergy, and in particular provided evidence for a genetic signal at the
MTFHS/BCL2A1 locus. Although the MWAS study showed that there was a
metabolomic difference between the allergic and non-allergic individuals. These
findings may lead to new personalised treatments based on a combination of
genotyping and metabolic characterization. The findings of our studies need
verification in independent cohorts.